DEVELOPMENT OF HEART

Dr. Shreetal Rajan Nair

Introduction

 Human heart starts to develop during the 3rd

week of embryonic life. Till then the needs of
the embryo are met through simple diffusion
of blood between the germ layers.
 Cardiogenesis in humans is associated with
complex morphogenetic events
 Area of discussion

 Anatomic
 Molecular
 Clinical aspects
 Cardiac development

 Early development
Formation of the trilaminar embryo
Origin of cardiogenic cells
Formation of bilateral heart fields
Formation of the heart tube
Folding of the heart tube
Looping of the heart tube
Cardiac developmental abnormalities
 The Beginnings…………(fetal
landmarks)
 Day 0 : Fertilisation forming zygote initiating
embryogenesis
 2 cell stage; 4 cell stage; morula
 Week 1 : implantation ( as a blastocyst)
 Week 2 : bilaminar stage (epiblast,hypoblast)
 Week 3 : gastrulation ;primitive
streak,notochord and neural plate begin to
form
 Week 4: heart begins to form.
Week 1 – beginning of
development
 Day 1-Fertilisation and formation of zygote
 Day 2 – 2 cell blastula
 Day 3 – 4 cell blastula
 Day 4 – morula ( 32 cell stage)
 Day 5 – blastocyst ( inner cell mass of
embryoblast and outer cell mass called
trophoblast)
 Day 6 - implantation
1st week
1st week
1st week
BLASTOCYST FORMATION
WEEK 2 – FORMATION OF
BILAMINAR EMBRYO
Week 3
Week 3
Week 3
SUMMARY- Early development

 Rule of 2’s for 2nd week

2 germ layers (bilaminar disk): epiblast,
hypoblast.
2 cavities :amniotic cavity,yolk sac
 Rule of 3’s for 3rd week
3 germ layers ( gastrula) :
ectoderm,mesoderm and endoderm
 Cardiac Embryogenesis
 Sequence of events

 Occurs towards the end of the 3rd week

 Day I8 - cardiac precursor cells seen in the form of
blood islands
 Day 20 - first intraembryonic blood vessels seen
 Day 21- Folding, heart tube formation,looping
 Day 22 – heart starts to beat, ebb and flow initially
 Day 28 – embryonic circulation established
 Cardiac development

 Early development
Formation of trilaminar embryo
Origin of cardiogenic cells
Formation of bilateral heart fields
Formation of the heart tube
Folding of the heart tube
Looping of the heart tube
Cardiac developmental abnormalities
  The developing blood vessels and heart tube
can be seen in an embryo at approximately 18
days .

 When looking down at this early embryo you

can see multiple blood islands dispersed
throughout the embryo.
Origin of cardiac precursor
cells

 The heart primordium arises predominantly

from the mesoderm in the cardiogenic
region of the trilaminar embryo.
Cardiac precursor cells

 First heart field (FHF)

 Second heart field (SHF)

 Proepicardium

 Cardiac neural crest cells

Cardiac precursor cells

 FHF

 SHF

 CNC

 Proepicardium
 Cardiac development

 Early development
Origin of cardiogenic cells
Formation of bilateral heart fields
Formation of the heart tubes
Folding of the heart tube
Looping of the heart tube
Cardiac development abnormalities
The concept of heart fields

 Two distinct mesodermal heart fields that

share a common origin appear to contribute
cells to the developing heart in a temporally
and spatially specific manner.
 Using special technologies to mark
progenitor cells two heart fields (the primary
and secondary) have been characterised.
 The heart tube derived from the primary
heart field may predominantly provide a
scaffold that enables a second population of
cells to migrate and expand into cardiac
chambers .
 These additional cells arise from an area
often referred to as the secondary heart field
(SHF), or anterior heart field, based on its
location anterior and medial to the crescent-
shaped primary heart field
 HEART FIELDS

 SHF cells cross the pharyngeal mesoderm

into the anterior and posterior portions,
contributing to the formation of the outflow
tract, future right ventricle, and atria
Pathophysiology
 Cardiac development

 Early development
Origin of cardiogenic cells
Formation of bilateral heart fields
Formation of the heart tube
Folding of the heart tube
Looping of the heart tube
Cardiac developmental abnormalities
 The flat germ disk transforms into a tubular
structure during the fourth week of
development
 This is achieved through a process of
differential growth causing the embryo to
fold in two different dimensions
Formation of the endocardial tube

 The heart initially forms

from two tubes located
bilaterally (on either side)
of the trilaminar embryo
in the cranial (head)
 This primitive, bilateral heart tubes each
contains an inner layer of endocardium, a
middle layer of cardiac jelly, and an outer
layer of myocardium region
Folding of the embryo

 1. Craniocaudal axis due to the more rapid

growth of the neural tube forming the brain
at its cephalic end. Growth in this direction
will cause the embryo to become convex
shaped.

 2.Lateral folding, causing the two lateral

edges of the germ disk to fold forming a
tube-like structure
THE CARDIOGENIC AREA

Heart Tube
Formation of the endocardial tube

 The primitive heart tubes

then fuse in the ventral
midline to form the linear
or straight heart tube in a
cranial to caudal direction
 Simultaneously the heart
tube shows a series of
dilatations.
From cranial to caudal these
are:
Bulbous cordis
Ventricle
Atrium
Sinus venosus
 The arterial trunk will divide to separate the pulmonary and systemic
supply.
 The bulbus and the ventricle will later differentiate into the right and left
ventricle
 Arterial end of the heart
 Bulbus cordis represents
the arterial end of heart. It
consists of

 proximal part called the conus

 a distal part called truncus
arteriosus.
 The truncus continues distally
with the aortic sac.
VENOUS END OF THE HEART TUBE

 The sinus venosus

represents the venous end
of the heart. One vitelline
vein from the yolksac; one
umbilical vein from the
placenta and one common
cardinal vein from the
bodywall ,joins each horn
of the sinus venosus.
 After the formation of the head fold, this tube
lies dorsal to the pericardial cavity and ventral
to the foregut.

 Splanchnopleuric mesoderm lining the dorsal

side of the pericardial cavity proliferates to
forma thick layer called the myoepicardial
mantle.
 When the invagination is complete, the
myoepicardial mantle completely surrounds
the heart tube

 It gives rise to the cardiac muscle

(MYOCARDIUM) and also to the visceral layer
of the pericardium (EPICARDIUM)
EXTERIOR OF THE HEART

 Heart tube is
suspended from the
dorsal wall of the
pericardial cavity by 2
layers of pericardium
that constitutes dorsal
mesocardium
 A hole forms in the dorsal
mesocardium which increases
in size.
 Gradually Mesocardium
disappears and the heart tube
lies free within the pericardial
cavity
 Mesocardium disappears to
form the transverse sinus of
the pericardium
 Cardiac development

 Early development
Origin of cardiogenic cells
Formation of bilateral heart fields
Formation of the heart tube
Folding of the heart tube
Looping of the heart tube
Cardiac developmental abnormalities
 Cardiac looping
 Looping of the heart tube allows the straight
heart tube to form a more complex structure
reminiscent of the adult heart. Most cardiac
looping occurs during the fourth week and
completes during the fifth week of development
 The linear heart tube develops differential
growth of the heart tube in comparison with
the foregut
 The direction of cardiac looping is
determined by an asymmetric signalling
system which affects the position of both
thoracic and abdominal contents
 In all vertebrates, there is differential growth
within the heart tube itself resulting in
posterior, leftward, slower growth and
anterior, rightward, faster growth resulting
in rightward looping. This positioning results
in the future right ventricle taking an anterior
and rightward location with reference to the
future left ventricle
 Further disproportionate growth of the heart
tube in comparison to the foregut results in
bending of the heart tube at the inflow as well
as within the ventricular segment eventually
positioning the inflow and future left
ventricular segments posteriorly and to the
left, with the future right ventricle and
outflow segments anteriorly and to the right
 The straight heart tube begins to
elongate with simultaneous growth
in the bulbus cordis and primitive
ventricle

 This forces the heart to bend

ventrally and rotate to the right,
forming a C-shaped loop with convex
side situated on the right.

 The ventricular bend moves caudally

and the distance between the
outflow and inflow tracts diminishes.

 The atrial and outflow poles

converge and myocardial cells are
added, forming the truncus
arteriosus
 Hence an S-shape is formed with the first
bend of the 'S' being the large ventricular
bend while the bend at the junction of the
atrium and sinus venosus forms the second 'S'
bend
The cardiac tube grows at a greater
longitudinal rate then the rest of the
embryo, causing it to fold. As it does
this
it falls to the right. This is known as
d-looping. It may fall to the left in an
l-loop: this will lead to a malformed
heart.

Below are chick embryo dissections

showing
the two types of loop.

normal d-loop l-loop

• The fold of the loop is principally at the junction of bulbus cordis and
ventricle. Note in panel C that the two end up side by side.
• The left ventricle will develop from the ventricle, and the right ventricle
will develop from the bulbus cordis. (And an l-loop will
result in ventricular inversion with the left ventricle on the right.
• Note also that the arterial trunk is above the developing right ventricle.
Time line of cardiogenesis
MOLECULAR ASPECTS IN
CARDIOGENESIS

 Transcriptional regulators

 Epigenetic regulation by microRNAs (miRNA)

ROLE OF RETINOIC ACID

 HENSON’S NODE which contains retinoic

acid, serves as an embryonic organizer that
confers information required to direct the
ultimate fate of mesodermal cells during
early embryogenesis.
 Exogenous retinoic acid is extremely
teratogenic at that stage
 Greatest effect is on the arterial pole.
 Cardiac development

 Early development
Origin of cardiogenic cells
Formation of bilateral heart fields
Formation of the heart tubes
Folding of the heart tube
Looping of the heart tube
Cardiac development abnormalities
Pathophysiology

 Abnormal left-right signalling

 Looping defects

 Defects due to abnormal migration of cells of

primary and secondary heart fields and of
cardiac neural crest
One disease – several
mechanisms – several genes
TRANSCRIPTIONAL REGULATORS
ABNORMALITIES OF DEVELOPMENT

 From Fertilization to Primitive Heart Tube

Abnormal development at this stage of
embryogenesis almost always results in
embryonic death because of the critical
nature of the early circulation to the further
growth and development of the embryo and
fetus.
DEFECTIVE EXPRESSION OF
TRANSCRIPTIONAL FACTORS

 Absence of Hand2 (dHAND) – results in

RV HYPOPLASIA or ABSENT RV
Abnormalities due to abnormal left-right
signalling and dorso ventral polarity

 HETEROTAXY SYNDROMES

 DORV

 DILV
Pathophysiology
 In humans, mirror-image reversal of left-right
asymmetry is often associated with normal
organ development ( simple dextrocardia or
situs inversus totalis) but discordance of thoracic
and visceral asymmetry universally results in
defective organogenesis, the most common
being heterotaxy syndrome.
HETEROTAXY SYNDROMES
Abnormalities of looping

 Ventricular Inversion with Transposition of

the Great Arteries
 There is currently considerable research in
animate models on the genes known to control
left-right development. Similarly, congenitally
corrected transposition of the great arteries is
thought to result from both an abnormality of
looping and of outflow tract development.
 Many other complex abnormalities involving
both ventricles and outflow tract are thought
to have at least some abnormality in the
looping process.
Defective migration of cells

 HYPOPLASIA OF RVOT/MPA - TOF

 ABSENCE OF RVOT/MPA- TA
 ABSENCE OF AORTO-PULMONARY SEPTUM
– TA
 MALALINGMENT OF AORTA AND LV –
ABNORMAL WEDGING -TOF
 ABNORMAL MYOCARDIAL
TRABECULATION- LV/RV NON COMPACTION
DEVELOPMENT ABNORMALITIES
 BIBLIOGRAPHY
1. Braunwald’s Heart Disease 9th edition
2. Hurst’s THE HEART 13th edition, chapter 9.
3. Moss and Adam’s Heart Disease , 7th edition
4. Harrison’s Text Book of Internal Medicine,18th edition
5. Embryology and Congenital Heart Disease,Paolo Angelini, MD
6. Cardiac Chamber Formation:Development, Genes, and Evolution ;
ANTOON F. M. MOORMAN AND VINCENT M. CHRISTOFFELS; 83: 1223–1267, 2003;
10.1152/physrev.00006.2003
7. Regulation of myocardial gene expression during heart development
Diego Franco ,Jorge Domínguez , María del Pilar de Castro , Amelia Aránega
Rev Esp Cardiol. 2002;55:167-84. - Vol. 55 Núm.02
8. Molecular embryology for an understanding of congenital heart diseases Hiroyuk i Yamagishi et
al. Anat Sci Int (2009) 84:88–94 ; Received: 27 May 2008 / Accepted: 16 June 2008 / Published
online: 7 April 2009; Japanese Association of Anatomists 2009
9. Cardiovascular Embryology ; R. Abdulla,G. A. Blew,M.J. Holterman ; Pediatr Cardiol
25:191–200, 2004
 Bibliography
10. Wherefore heart thou? Embryonic origins of cardiogenic mesoderm; Katherine E.
Yutzey ,Margaret L. Kirby , Developmental Dynamics , volume 223 ;issue 3;pages
307–320, March 2002